PROJECT SUMMARY The current strategy of breast cancer screening is mainly based on age, while there is intense debate in the last two decades on screening frequency and age to start screening. This age-based screening strategy could be an important reason for cancer health disparity because African Americans are more likely to have young- onset and estrogen receptor negative breast cancer than other ethnic groups in the US. Risk-stratified breast cancer screening strategy is a paradigm shift to reduce racial disparity in breast cancer outcomes. Increasing number of common genetic variants have been identified in genome-wide association studies, and polygenic risk scores (PRS) based on these common variants are yet to be evaluated in diverse populations. Moreover, it is important to incorporate ethnic-specific PRS with high-penetrance or intermediate-penetrance genes such as BRCA1/2, as well as non-genetic risk factors in order to have a comprehensive risk assessment tool in the clinic. Once women who are at high risk for breast cancer are identified, appropriate intervention to reduce risk should follow. Culturally, removal of healthy breasts is less acceptable to high- risk African American and Latino women, yet there appears to be a high burden of inherited breast cancer in these communities. There is currently no consensus on the best screening strategy for women at very high risk, although dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) appears promising. False positive rates and cost, among others, are important barriers to widespread adoption of screening with DCE-MRI, especially for high risk underserved minority populations. To achieve health equity, the proposed planning project will evaluate the performance of ethnic-specific PRS in combination with existing risk prediction models using the Chicago Multiethnic Epidemiologic Breast Cancer Study (ChiMEC) (Aim 1). We will conduct panel sequencing in 1000 women with breast cancer and 1000 controls, with half being African Americans and half Caucasians. We will also develop efficient and faster MRI protocols for a Personalized Risk-based Imaging Surveillance Model (PRISM) for high-risk women of African, European and Hispanic Ancestry (Aim 2). We will test the diagnostic equivalency of two novel MRI protocols including abbreviated MRI (AB-MRI) and ultrafast dynamic contrast enhanced (DCE) MRI against the full DCE-MRI protocol. 400 women at high risk for breast cancer will be screened biannually with abbreviated and ultrafast DCE-MRI protocols and annual mammogram over a three- year period. We plan to our novel MRI protocol to a large national prospective clinical trial comparing personalized screening with conventional age-based screening strategy.